Process for the preparation of fibrates

ABSTRACT

A process for the preparation of fibrates of formula I  
                 
 
     in which R 1  is a halogen atom, a 2,2-dichloro-cyclopropyl group, a (4-chlorophenyul)-hydroxymethyl group, a-4-chlorobenzoyl group or a 2-(4-chlorobenzamido)-ethyl group, and R 2  is hydrogen or a C 1 -C 4  alkyl group.

[0001] The present invention relates to a process for the preparation of fibrates of formula (I)

[0002] wherein R₁ is a halogen atom, a 2,2-dichloro-cyclopropyl group, a (4-chlorophenyl)-hydroxymethyl group, a 4-chlorobenzoyl group or a 2-(4-chlorobenzamido)-ethyl group, and

[0003] R₂ is hydrogen or a C₁-C₄ alkyl group.

[0004] The compounds of formula (I) are known medicaments with hypocholesterolemic activity. In particular, fenofibrate, clofibrate and ciprofibrate have been widely used in clinic for some time in the treatment of dyslipidemias. The preparation thereof is disclosed, for example, in GB 860,303 (clofibrate), GB 1,415,295 (fenofibrate), GB 1,539,897.

[0005] According to an improved process for the preparation of the fibrates of formula (I), disclosed in EP-B-245,156 (Fournier, 11.11.1987), an alkyl 2-bromo-2-methyl-propionate of formula (II)

[0006] wherein R₂ is as defined above,

[0007] is reacted with a substituted phenol of formula (III)

[0008] wherein R₁ is as defined above,

[0009] in the absence of solvent and in the presence of a potassium carbonate excess, at temperatures above 120° C. for times longer than 2 hours.

[0010] It has now been found, and this is the object of the present invention, that the fibrates of formula (I) can advantageously be prepared by reacting the same compounds of formulae (II) and (III), as defined above, in the presence of potassium bicarbonate and of a solvent selected from C₁-C₄ alcohols and ketones at temperatures ranging from room temperature to 100° C.

[0011] The process of the invention is particularly suitable for the preparation of fenofibrate (compound of formula I wherein R₁ is 4-chloro-benzoyl).

[0012] Isopropanol is preferably used as the reaction solvent.

[0013] Potassium bicarbonate can be used in amounts sufficient to neutralize the halo acid formed during the reaction. The compound of formula (II) is preferably used in a stoichiometric excess to the compound of formula (III).

[0014] The solvent and the unreacted compound of formula (II) are evaporated off the reaction mixture and the residue is crystallized from a suitable solvent.

[0015] Compared with the method described in EP 245,156, the process of the present invention allows therefore to recover the reaction product directly from the reaction medium, without preventive purification of the crude product. Furthermore, there is no need for an acid excess to neutralize the potassium salt. As a consequence, the process of the invention is cost-saving and industrially advantageous compared with those of the prior art, in particular that disclosed in EP 245,156.

[0016] The following example illustrates the process of the invention in greater detail.

EXAMPLE

[0017] Isopropanol (400 ml), 4-chloro-4′-hydroxy-benzophenone (100 g, 0.431 mols), potassium bicarbonate (78 g, 0.78 mols), isopropyl α-bromo-isobutyrate (180 g, 0.865 mols) are loaded into a 21 round-bottom flask at room temperature.

[0018] The solvent is refluxed (82-84° C. inner temperature) for 36 hours. After completion of the reaction, the solvent and the isopropyl α-bromo-isobutyrate excess are evaporated off under vacuum. The residue is taken up into acetone (400 ml) and insolubles are filtered off at room temperature. The filtered solution is concentrated to a residue and diluted with isopropyl alcohol (400 ml), then cooled at a temperature of 0-5° C. and the product is left to crystallize for at least 8 hours.

[0019] About 130 g of a product which meets the pharmacopoeia requirements are obtained (86% yield). 

1. A process for the preparation of fibrates of formula (I)

wherein R₁ is a halogen atom, a 2,2-dichloro-cyclopropyl group, a (4-chlorophenyl)-hydroxymethyl group, a 4-chlorobenzoyl group or a 2-(4-chlorobenzamido)-ethyl group, and R₂ is hydrogen or a C₁-C₄ alkyl group, which process comprises reacting an alkyl 2-bromo-2-methyl-propionate of formula (II)

wherein R₂ is as defined above, with a substituted phenol of formula (III)

wherein R₁ is as defined above, in the presence of potassium bicarbonate and of a solvent selected from C₁-C₄ alcohols and ketones, at temperatures ranging from room temperature to 100° C.
 2. A process as claimed in claim 1 for the preparation of fenofibrate.
 3. A process as claimed in claim 1 or 2 wherein the reaction solvent is isopropanol.
 4. A process as claimed in any one of claims 1 to 3, wherein the final product is recovered directly from the reaction medium, after evaporation of the solvent and crystallization. 